tbuckley/cabot-search huggingface dataset:
Translational immunoPET imaging using a radiolabeled GD2-specific antibody in neuroblastoma
Authors: Julia Schmitt, Johannes Schwenck, Andreas Maurer, Mirko Przybille, Dominik Sonanini, Gerald Reischl, Jöri E. Wehrmüller, Leticia Quintanilla-Martinez, Stephen D. Gillies, Marcel A. Krueger, Juergen F. Schaefer, Christian la Fougère, Rupert Handgretinger, Bernd J. Pichler
Journal: Theranostics (2022)

Background: Antibodies targeting surface expressed disialoganglioside GD2 are increasingly used in neuroblastoma immunotherapy and might also have potential for use in radioimmunotherapy.As such targeted treatments might benefit from a dedicated theranostic approach, we studied the influence of radiolabeling on the binding characteristics of ch14.18 antibodies produced by Chinese hamster ovary (CHO) cells and evaluated the benefit of GD2-ImmunoPET as a potential tool for therapy planning.Methods: 64 Cu was used to reduce radiation burden, which is of high importance especially in a pediatric patient population. 64Cu-labeling was accomplished using the chelators NOTA-or DOTAGA-NCS.Radiolabeled antibodies were characterized in vitro.[ 64 Cu]Cu-DOTAGA-ch14.18/CHO was studied in a neuroblastoma mouse model (subcutaneous CHP-134 xenografts).In vivo PET and MR images were acquired at 3 h, 24 h, and 48 h p.i.The specificity of binding was verified using GD2-negative tumors (HEK-293 xenografts), a control antibody and in vivo blocking.A first translational application was performed by PET/MRI in a patient with metastasized neuroblastoma.Results: Radiolabeling at an antibody-to-chelator ratio ≥1:10 yielded a product with a radiochemical purity of ≥90% and a specific activity of 0.2-1.0MBq/µg.Radiochelation was stable over 48 h in PBS, mouse serum or EDTA, and 50.8 ± 3.5% and 50.8 ± 2.0% of the radiolabeled conjugates, prepared at antibody-to-chelator ratios of 1:10 or 1:15, were immunoreactive.In vivo, highly specific accumulation (31.6 ± 5.8% ID/g) in neuroblastoma was shown preclinically.Clinical PET/MR scans using [ 64 Cu]Cu-NOTA-ch14.18/CHO(NOTA used for safety reasons) could visualize neuroblastoma metastases.Conclusions: In vivo, 64 Cu-labeled ch14.18/CHO is suitable for specific identification of neuroblastoma in PET.A first patient PET indicated the feasibility of the method for clinical translation and the potential utility in image-guided therapy.
MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation
Authors: Jyun-Ni Chi, Jhih-Yu Yang, Chia-Hsin Hsueh, Ching-Yi Tsai, Huai-Chia Chuang, Tse-Hua Tan
Journal: Theranostics (2022)

Rationale: GLK (MAP4K3) activates PKCθ-IKKβ axis in T-cell activation and induces IL-17A-mediated autoimmune diseases. Attenuation of Treg differentiation and function by GLK could also contribute to autoimmune diseases. Methods: We analyzed the roles of GLK and IKKβ in Treg differentiation and function using T-cell-specific GLK transgenic mice and IKKβ conditional knockout mice. The mechanism of GLK/IKKβ-mediated attenuation of Treg differentiation/function was studied by chromatin-immunoprecipitation, reporter assays, in vitro kinase assays, protein-protein interaction assays, mass spectrometry, confocal microscopy, flow cytometry, and single-cell RNA sequencing (scRNA-seq) analysis. Results: We found that GLK signaling inhibited Foxp3 transcription by blocking the function of the transcription factor FoxO1. Mechanistically, GLK directly phosphorylated and activated IKKβ at Ser733 in a PKCθ-independent manner. The phospho-IKKβ Ser733 induced FoxO1 Ser319 phosphorylation and nuclear export, leading to Foxp3 downregulation. Consistently, scRNA-seq analyses showed that Foxp3 mRNA levels were inversely correlated with FoxO1 mRNA levels in GLK transgenic CD4+ T cells. Conclusions: GLK-IKKβ-FoxO1 signaling axis inhibits Foxp3 transcription, leading to reduction of Treg differentiation and suppressive activity, as well as induction of autoimmune disease.
DNA aptamers inhibit SARS-CoV-2 spike-protein binding to hACE2 by an RBD- independent or dependent approach
Authors: Achut Prasad Silwal, Siddhartha Kalpa Samadhi Thennakoon, Satya Prakash Arya, Rick Mason Postema, Raunak Jahan, Chien Minh Tran Phuoc, Xiaohong Tan
Journal: Theranostics (2022)

Objective: Nobody knows when the COVID-19 pandemic will end or when and where the next coronavirus will outbreak. Therefore, it is still necessary to develop SARS-CoV-2 inhibitors for different variants or even the new coronavirus. Since SARS-CoV-2 uses its surface spike-protein to recognize hACE2, mediating its entry into cells, ligands that can specifically recognize the spike-protein have the potential to prevent infection. Methods: We have recently discovered DNA aptamers against the S2-domain of the WT spike-protein by exploiting the selection process called SELEX. After optimization, among all candidates, the aptamer S2A2C1 has the shortest sequence and the best binding affinity toward the S2-protein. More importantly, the S2A2C1 aptamer does not bind to the RBD of the spike-protein, but it efficiently blocks the spike-protein/hACE2 interaction, suggesting an RBD-independent inhibition approach. To further improve its performance, we conjugated the S2A2C1 aptamer with a reported anti-RBD aptamer, S1B6C3, using various linkers and constructed hetero-bivalent fusion aptamers. Binding affinities of mono and fusion aptamers against the spike-proteins were measured. The inhibition efficacies of mono and fusion aptamers to prevent the hACE2/spike-protein interaction were determined using ELISA. Results: Anti-spike-protein aptamers, including S2A2C1 and S1B6C3-A5-S2A2C1, maintained high binding affinity toward the WT, Delta, and Omicron spike-proteins and high inhibition efficacies to prevent them from binding to hACE2, rendering them well-suited as diagnostic and therapeutic molecular tools to target SARS-CoV-2 and its variants. Conclusions: Overall, we discovered the anti-S2 aptamer, S2A2C1, which inhibits the hACE2/spike-protein interaction via an RBD-independent approach. The anti-S2 and anti-RBD aptamers were conjugated to obtain the fusion aptamer, S1B6C3-A5-S2A2C1, which recognizes the spike-protein by an RBD-dependent approach. Our strategies, which discovered aptamer inhibitors targeting the highly conserved S2-protein, as well as the design of fusion aptamers, can be used to target new coronaviruses as they emerge.
XBP1 is required in Th2 polarization induction in airway allergy
Authors: Xianhai Zeng, Xiaojun Xiao, Suqin Hu, Weiyi He, Gaohui Wu, Xiaorui Geng, Jialiang Fan, Longpeng Ma, Jiangqi Liu, Zhiqiang Liu, Pingchang Yang
Journal: Theranostics (2022)

Rationale:Th2 polarization plays a central role in the pathogenesis of allergic diseases such as airway allergy.The underlying mechanism is not fully understood yet.X-box-binding protein-1 (XBP1) can regulate immune cell activities upon exposing stressful events.The role of XBP1 in the development of Th2 polarization has not yet been explored.Methods: Mice carrying Xbp1-deficient CD4 + T cells were employed to observe the role of XBP1 in the induction of airway allergy.A cell culture model was established to evaluate the role of XBP1 in facilitating the Th2 lineage commitment.Results: We found that Xbp1 ablation in CD4 + T cells prevented induction of Th2 polarization in the mouse airway tract.XBP1 was indispensable in the Th2 lineage commitment.XBP1 mediated the effects of 3-methyl-4-nitrophenol (MNP) on facilitating inducing antigen-specific Th2 response in the airways.Exposure to MNP induced expression of XBP1 in CD4 + T cells.RhoA facilitated the binding between XBP1 and GATA3 in CD4 + T cells.XBP1 induced GATA3 phosphorylation to promote the Il4 gene transcription.Modulation of the RhoA/XBP1 axis mitigated experimental allergic response in the mouse airways.Conclusions: A potential therapeutic target, XBP1, was identified in this study.XBP1 was required in the development of skewed Th2 response in the airways.Inhibiting XBP1 alleviated Th2 polarization-related immune inflammation in the airways.The data suggest that inhibiting XBP1 has the translation potential for the treatment of airway allergy.
Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice: Erratum
Authors: Ya-Jie Lv, Yi Yang, Bing-Dong Sui, Cheng-Hu Hu, Pan Zhao, Li Liao, Ji Chen, Li-Qiang Zhang, Tong-Tao Yang, Shao-Feng Zhang, Yan Jin
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.23620.].
Human Umbilical Cord MSCs as New Cell Sources for Promoting Periodontal Regeneration in Inflammatory Periodontal Defect: Errautm
Authors: Fengqing Shang, Shiyu Liu, Leiguo Ming, Rong Tian, Fang Jin, Yin Ding, Yongjie Zhang, Hongmei Zhang, Zhihong Deng, Yan Jin
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.19888.].
Bone tissue engineering supported by bioprinted cell constructs with endothelial cell spheroids
Authors: WonJin Kim, Chul Ho Jang, GeunHyung Kim
Journal: Theranostics (2022)

In bone tissue engineering, efficient formation of vascularized bone tissue is a challenging issue. Here, we introduce a new strategy for effectively using multiple cells laden in a hybrid structure, such as endothelial cell (EC) spheroids and homogeneously distributed human adipose stem cells (hASCs) for bone regeneration.
Raman spectroscopy reveals phenotype switches in breast cancer metastasis
Authors: Santosh Kumar Paidi, Joel Rodriguez Troncoso, Mason G. Harper, Zhenhui Liu, Khue G. Nguyen, Sruthi Ravindranathan, Lisa Rebello, David E. Lee, Jesse D. Ivers, David A. Zaharoff, Narasimhan Rajaram, Ishan Barman
Journal: Theranostics (2022)

The accurate analytical characterization of metastatic phenotype at primary tumor diagnosis and its evolution with time are critical for controlling metastatic progression of cancer.Here, we report a label-free optical strategy using Raman spectroscopy and machine learning to identify distinct metastatic phenotypes observed in tumors formed by isogenic murine breast cancer cell lines of progressively increasing metastatic propensities.Methods: We employed the 4T1 isogenic panel of murine breast cancer cells to grow tumors of varying metastatic potential and acquired label-free spectra using a fiber probe-based portable Raman spectroscopy system.We used MCR-ALS and random forests classifiers to identify putative spectral markers and predict metastatic phenotype of tumors based on their optical spectra.We also used tumors derived from 4T1 cells silenced for the expression of TWIST, FOXC2 and CXCR3 genes to assess their metastatic phenotype based on their Raman spectra. Results:The MCR-ALS spectral decomposition showed consistent differences in the contribution of components that resembled collagen and lipids between the non-metastatic 67NR tumors and the metastatic tumors formed by FARN, 4T07, and 4T1 cells.Our Raman spectra-based random forest analysis provided evidence that machine learning models built on spectral data can allow the accurate identification of metastatic phenotype of independent test tumors.By silencing genes critical for metastasis in highly metastatic cell lines, we showed that the random forest classifiers provided predictions consistent with the observed phenotypic switch of the resultant tumors towards lower metastatic potential.Furthermore, the spectral assessment of lipid and collagen content of these tumors was consistent with the observed phenotypic switch.Conclusion: Overall, our findings indicate that Raman spectroscopy may offer a novel strategy to evaluate metastatic risk during primary tumor biopsies in clinical patients.
Dedifferentiated Schwann cell-derived TGF-β3 is essential for the neural system to promote wound healing
Authors: Min-Yi Ou, Poh-Ching Tan, Yun Xie, Kai Liu, Yi-Ming Gao, Xiao-Sheng Yang, Shuang-Bai Zhou, Qing-Feng Li
Journal: Theranostics (2022)

Rationale: Wound healing is among the most complicated physiological processes and requires the synchronization of various cell types with distinct roles to re-establish the condition of the original skin.Patients affected by peripheral neuropathies often experience failure to heal.Loss of Schwann cells (SCs), a crucial population of peripheral nervous system cells in skin, may contribute to chronic wounds.However, the role of SCs in wound healing are poorly understood.Methods: The activity of SCs was investigated by using a cell atlas of the wound healing process, which was generated by integrating single-cell RNA sequencing (scRNA-seq) libraries covering different states of mouse back skin.The results of in silico analysis were validated by in vitro cell culture and in vivo mouse model.Selective inhibitors and conditional RNAi by virus transfection were utilized to investigate the role of SCs in wound healing.Findings from mouse experiments were further verified in scRNA-seq analysis of diabetic patients.Results: Our in silico analysis revealed the heterogeneous cellular components of skin and the dynamic interactions of neural crest derived cells (NCs) with other cell types.We found that SCs dedifferentiated at an early stage of wound repair with upregulated Wnt signaling.We also identified dedifferentiated SC (dSC) defect in diabetic wounds in both mouse and human.Wnt inhibition at the wound site repressed SC dedifferentiation, leading to defective repair.Furthermore, dSCs derived TGF-β3, which is context-dependent, promoted the migration of fibroblasts and keratinocytes.Moreover, TGF-β3 supplementation enhanced the healing of chronic wounds in diabetic mice with impaired SCs.Conclusion: Our study thus advances the understanding of the roles of neural-derived cells in skin regeneration and suggests a potential therapeutic strategy for wound healing disorders.
RNA <i>N<sup>6</sup></i>-methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer
Authors: Brandon Tan, Keren Zhou, Wei Liu, Emily Prince, Ying Qing, Yangchan Li, Li Han, Xi Qin, Rui Su, Sheela Pangeni Pokharel, Lu Yang, Zhicong Zhao, Chao Shen, Wei Li, Zhenhua Chen, Zheng Zhang, Xiaolan Deng, Andrew Small, Kitty Wang, Keith Leung, Chun-Wei Chen, Binghui Shen, Jianjun Chen
Journal: Theranostics (2022)

RNA N 6 -methyladenosine (m 6 A) modification and its regulators fine tune gene expression and contribute to tumorigenesis.This study aims to uncover the essential role and the underlying molecular mechanism(s) of the m 6 A reader YTHDC1 in promoting triple negative breast cancer (TNBC) metastasis.Methods: In vitro and in vivo models were employed to determine the pathological function of YTHDC1 in TNBC metastasis.To identify bona fide YTHDC1 target RNAs, we conducted RNA-seq, m 6 A-seq, and RIP-seq, followed by integrative data analysis and validation assays.Results: By analyzing The Cancer Genome Atlas (TCGA) dataset, we found that elevated expression of YTHDC1 is positively correlated with poor prognosis in breast cancer patients.Using a mammary fat pad mouse model of TNBC, YTHDC1 significantly promoted lung metastasis of TNBC cells.Through multiple transcriptome-wide sequencing and integrative data analysis, we revealed dysregulation of metastasis-related pathways following YTHDC1 depletion and identified SMAD3 as a bona fide YTHDC1 target RNA.Depletion of YTHDC1 caused nuclear retention of SMAD3 mRNA, leading to lower SMAD3 protein levels.Loss of YTHDC1 led to impaired TGF-β-induced gene expression, leading to inhibition of epithelial-mesenchymal transition (EMT) and suppressed TNBC cell migration and invasion.SMAD3 overexpression was able to restore the response to TGF-β in YTHDC1 depleted TNBC cells.Furthermore, we demonstrated that the oncogenic role of YTHDC1 is mediated through its recognition of m 6 A as m 6 A-binding defective mutants of YTHDC1 were unable to rescue the impaired cell migration and invasion of YTHDC1 knockout TNBC cells.Conclusions: We show that YTHDC1 plays a critical oncogenic role in TNBC metastasis through promoting the nuclear export and expression of SMAD3 to augment the TGF-β signaling cascade.Overall, our study demonstrates that YTHDC1 is vital for TNBC progression by enhancing TNBC cell survival and TGF-β-mediated EMT via SMAD3 to enable the formation of distant metastasis and highlights the therapeutic potential of targeting the YTHDC1/m 6 A/SMAD3 axis for TNBC treatment.
Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9<sup>+</sup> renal tubular cells
Authors: Jian-Wen Chen, Meng-Jie Huang, Xiao-Niao Chen, Ling-Ling Wu, Qing-Gang Li, Quan Hong, Jie Wu, Fei Li, Liang-Mei Chen, Yu Dong, Guang-Yan Cai, Xue-Yuan Bai, Zongjin Li, Xiang-Mei Chen
Journal: Theranostics (2022)

Background: Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease.Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI.Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm.Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated.Methods: AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration.To further determine the function of EGR1, Egr1 -/-mice were applied.Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9.Results: EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database.Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration.Further experiments affirmed that genetic inhibition of Egr1 aggravates the severity of AKI in mouse models.Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the Sox9 gene, thus promoting SOX9 + cell proliferation by activating the Wnt/β-catenin pathway.Conclusions: Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.
Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression
Authors: Na Ning, Si Zhang, Qi Wu, Xun Li, Dong Kuang, Yaqi Duan, Minghui Xia, Huicheng Liu, Junmei Weng, Hongping Ba, Zhaohui Tang, Xiang Cheng, Heng Mei, Liu Huang, Qilin Ao, Guoping Wang, Yu Hu, Arian Laurence, Jing Wang, Guihua Wang, Xiang-Ping Yang
Journal: Theranostics (2022)

Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL).Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models.Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined.Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro.The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells.The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients.Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax.Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax.Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation.Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1.In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1.Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis.Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.
A surrogate marker for very early-stage tau pathology is detectable by molecular magnetic resonance imaging
Authors: Parag Parekh, Qingshan Mu, Andrew Badachhape, Rohan Bhavane, Mayank Srivastava, Laxman Devkota, Xianwei Sun, Prajwal Bhandari, Jason L. Eriksen, Eric Tanifum, Ketan Ghaghada, Ananth Annapragada
Journal: Theranostics (2022)

The abnormal phosphorylation of tau is a necessary precursor to the formation of tau fibrils, a marker of Alzheimer's disease.We hypothesize that hyperphosphorylative conditions may result in unique cell surface markers.We identify and demonstrate the utility of such surrogate markers to identify the hyperphosphorylative state.Methods: Cell SELEX was used to identify novel thioaptamers specifically binding hyperphosphorylative cells.Cell surface vimentin was identified as a potential binding target of the aptamer.Novel molecular magnetic resonance imaging (M-MRI) probes using these aptamers and a small molecule ligand to vimentin were used for in vivo detection of this pre-pathological state.Results: In a mouse model of pathological tau, we demonstrated in vivo visualization of the hyperphosphorylative state by M-MRI, enabling the identification at a pre-pathological stage of mice that develop frank tau pathology several months later.In vivo visualization of the hyperphosphorylative state by M-MRI was further validated in a second mouse model (APP/PS1) of Alzheimer's disease again identifying the mutants at a pre-pathological stage.Conclusions: M-MRI of the hyperphosphorylative state identifies future tau pathology and could enable extremely early-stage diagnosis of Alzheimer's disease, at a pre-patholgical stage.